The present invention concerns new processes for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
The 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazole compounds of formula I 
or a pharmaceutically acceptable salt thereof, wherein:
R1, R2, R4, R5, R6, R8, R9, R12 and R13 are each independently hydrogen, alkyl, aryl or heteroaryl;
R3, R7, R10 and R11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; and
X is CH or N,
are novel, potent inhibitors of cyclin dependent kinases (cdks). They are useful in the therapy of proliferative diseases, for example, cancer, inflammation, autoimmune diseases such as arthritis, viral diseases, fungal diseases, chemotherapy-induced alopecia, neurodegenerative disorders such as Alzheimer""s disease and cardiovascular disease. More specifically, the compounds of formula I are useful in the treatment of a variety of cancers such as bladder, breast, colon, kidney, liver and lung cancers.
The preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles of formula I, has been described (K. S. Kim et al., WO 99/24416, May 20, 1999 and corresponding U.S. Pat. No. 6,040,321).
4-Formylphenylacetic acid has been previously prepared from ethyl phenylacetate in four steps which provided  less than 15% overall yield (J. W. Baker et al., J. Chem. Soc. 1956, 404).
The reaction of 4-bromophenylacetic acid or ester with alkyl acrylates using palladium catalysts to give 4-(2-alkoxycarbonylvinyl)phenylacetic acid or ester has been previously reported in the literature (J. W. Tilley et al., J. Med. Chem. 1991, 34, 1125; A. Cerri et al., J. Heterocycl. Chem. 1993, 30, 1581). The oxidation of xcex2-arylacrylates to give aryl aldehydes has also been reported (G. Cainelli et al., Synthesis, 1989, 47; D. G. Lee et al., Can. J. Chem. 1972, 50; D. G. Lee et al., Liebigs Ann. Chem. 1993, 503; S. Antus et al., Liebigs Ann. Chem. 1993, 105).
This invention concerns new efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs. The processes involve new strategy for the preparation of formylarylacetic acids, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.